Activities of human exonuclease 1 that promote cleavage of transcribed immunoglobulin switch regions.
Eukaryotic exonuclease 1 functions in replication, recombination, mismatch repair, telomere maintenance, immunoglobulin (Ig) gene class switch recombination, and somatic hypermutation. The enzyme has 5'-3' exonuclease, flap endonuclease, and weak RNaseH activity in vitro, but it has been difficult to reconcile these activities with its diverse biological functions. We report robust cleavage by human exonuclease 1 of transcribed G-rich DNA sequences with potential to form G loops and G4 DNA. Predicted Ig switch recombination intermediates are substrates for both exonucleolytic and 5' flap endonucleolytic cleavage. Excision is nick-dependent and structure-dependent. These results lead to a model for exonuclease 1 function in class switch recombination in which cleavage at activation-induced deaminase (AID)-initiated nicks produces gaps that become substrates for further attack by AID and subsequent repair.
Vallur
Aarthy C
AC
Departments of Immunology and Biochemistry, University of Washington Medical School, Seattle, WA 98195-7650, USA.
Maizels
Nancy
N
D000818:Animals; D003564:Cytidine Deaminase / Q000378:metabolism*; D045643:DNA Repair Enzymes / Q000378:metabolism* / Q000502:physiology; D005090:Exodeoxyribonucleases / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D006868:Hydrolysis; D017578:Immunoglobulin Class Switching / Q000235:genetics; D007134:Immunoglobulin Switch Region / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D014158:Transcription, Genetic; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
C114331:EXO1 protein, human; D005090:Exodeoxyribonucleases; C028450:exodeoxyribonuclease I; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase; D045643:DNA Repair Enzymes